Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

TY - JOUR

T1 - Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

AU - Shehata, Mohamed A

AU - Jensen, Anne Cathrine Nøhr

AU - Lissa, Delphine

AU - Bisig, Christoph

AU - Isberg, Vignir

AU - Andersen, Kirsten B

AU - Harpsøe, Kasper

AU - Björkling, Fredrik

AU - Bräuner-Osborne, Hans

AU - Gloriam, David E

PY - 2016/11/10

Y1 - 2016/11/10

N2 - GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson's disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization.

AB - GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson's disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization.

U2 - 10.1038/srep36681

DO - 10.1038/srep36681

M3 - Journal article

C2 - 27830715

SN - 2045-2322

VL - 6

SP - 1

EP - 13

JO - Scientific Reports

JF - Scientific Reports

M1 - 36681

ER -